This is an amended application for a renewal consideration of a Program Project Grant, "Molecular Mechanisms of Contraction." The unifying theme of this renewal application for a Program Project is the same is in previous competitive renewal applications viz., regulation of excitation-contraction- coupling (EC-coupling) with the primary focus on calcium-dependent processes. The projects are designed to elucidate fundamental molecular regulatory processes that characterize normal cardiac function, and events that lead to hypertrophy and heart failure in molecularly engineered mice. The latter exhibit intriguing phenotypes that have led to new insights and processes that may be relevant to human disease. An understanding of the biochemical, physiological and pharmacological factors involved in normal cardiac contractile functions and in disease processes, should provide a framework for the understanding of cardiac regulation on a molecular level and development of rational therapeutic measures to prevent or reverse heart failure. Three projects include studies on the human voltage-dependent calcium channel, the beta-adrenergic system and coupling to G proteins, and isoforms of tropomyosin, a regulatory protein of the thin filament of the cardiac sarcomere. The projects interdigitate and focus on fundamental molecular and cellular mechanisms. Techniques on mouse physiology and pharmacology and receptor binding are emphasized. Potential polymorphisms found in the human population and relationships to cardiac muscle dysfunction form an important part of the Program project. The scientific Core, dedicated specifically to techniques of mouse physiology, pharmacology and morphology/pathology, is the essential linch- pin for this Program Project.